Chemically Clopidogrel bisulfate is methyl (+)-(S)-α(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
One of Clopidogrel bisulfate structural formula is as follows:

Clopidogrel bisulfate is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. In addition to ADP, Clopidogrel also block the release of ADP from the platelet activation caused by the proliferation, inhibit platelet aggregation induced by other agonists. Clopidogrel did not inhibit phosphodiesterase activity. Clopidogrel irreversibly modified by platelet ADP receptor.
Plavix (Clopidogrel Bisulphate tablet), a product of Sanofi-Aventis Company Limited, has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular accidents resulting in death, and decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. Plavix also has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke.
In the Chinese market, Clopidogrel Bisulphate tablet of Shenzhen Salubris Pharmaceutical Company Limited-Talcom (the equivalent of 25 mg Clopidogrel) is used for preventing and treating heart, brain and other artery circulatory disturbance disease caused by platelet aggregate status.
U.S. Pat. No. 5,576,328 describes a method of preventing the occurrence of a secondary ischemic event by administration of Clopidogrel and one kind of medicinal acid salt and is incorporated herein as a reference.
U.S. Pat. No. 4,847,265 especially describes dextro-rotatory enantiomer of Clopidogrel and its pharmaceutically acceptable salt with platelet aggregation inhibiting activity and a process for preparation of this compound starting from the racemate and the pharmaceutical compositions containing it.
U.S. Pat. No. 6,429,210 and No. 6,504,030 claimed Clopiodgrel Bisulphate polymorphic form II and its preparation method.
U.S. Pat. No. 6,767,913 claimed the preparation method and pharmaceutics of Clopidogrel Bisulphate containing X Ray powder diffraction pattern with characteristic peaks and polymorphic form III, IV, V, VI, as well as preparation method of form II.
WO 2006/044548 provided solid premix based on containing Clopidogrel, there are at least one pharmaceutical excipient which is adsorbed on it.
WO 2004/098593 provided amorphous Clopidogrel sulphate, either or both of calcium stearate and magnesium stearate and one non-hygroscopic additive and at least one excipient.
WO 2007/008045 provided pharmaceutical containing Clopidogrel Bisulfate and pregelatinized starch.
WO 2008/059298 provided a formula for solid preparations containing Clopidogrel Bisulphate crystal form I as active ingredient, microcrystalline cellulose and aerosil as filler and adhesive, a disintegrant and a lubricant as other excipients.
The existing clopidogrel bisulphate tablet contains Clopidogrel Bisulphate, diluent, adhesive, glidant, disintegrant, and lubricant.
Plavix, manufactured by Sanofi-Aventis pharmaceutical Company Limited contains Mannitol, Microcrystalline cellulose, Hydroxy propyl cellulose, Polyethylene glycol 6000 and Hydrogenated castor oil in addition to Clopidogrel Bisulphate (From Plavix Label)
Clopidogrel being a thieno [3, 2-c] derivative exhibits rapid degradation when co-processed with certain excipients, such as alkaline metal containing salts for example magnesium stearate etc. Some patents do not use magnesium stearate to prevent Clopidogrel bisulfate from degrading.
Clopidogrel Bisulfate tablets of Shenzhen Salubris Pharmaceutical Company Limite-Taijia contains glycerol palmitic acid stearate and Colloidal Silicon Dioxide, preparing through grinding equal increments in order to increase the stability and safety of solid dosage form (from CN100400035).
U.S. Pat. No. 6,914,141 claimed one medicinal tablet which contain Clopidogrel Bisulphate and lubricant selected from zinc stearate, stearic acid and sodium stearoyl fumaric acid.
U.S. Pat. No. 4,591,592 claim ascorbic acid, benzoic acid, tartaric acid , fumaric acid ,and citric acid can prevent degradation of the drug.
WO 0001364 claimed polyethylene glycol instead of magnesium stearate as lubricant. WO 2007/091279 claimed glyceryl dibehenate as lubricant. United States publication US20090264460 claimed one or some of stearic acid, magnesium stearate, zinc stearate, calcium stearate, sodium stearoyl fumaric acid, glycery behenate or hydrogenated vegetable oil as lubricant. Clopidogrel bisulfate contains a carbolic acidester easily hydrolyses in the presence of Clopidogrel acid (impurity A).
WO 2005/048992 claimed the formula of Clopidogrel Mesylate, Hydrobromide and Hydrochloride, and suggests coating Clopidogrel particles, granules or agglomerates with polyvinyl acetate or Polyvinyl alcohol and one hydrophobic ingredient such as hydrogenated vegetable oil.
WO 2008/072939 and WO 2008/072836 claimed that Clopidogrel having superior storage stability comprising Clopidogrel represented by the formula (1) below and β-cyclodextrin at an equivalence ratio from 1:1.0 to 1:2.5.
The biggest difficulty for Clopidogrel tablet manufacturing is that tablets containing Clopidogrel bisulfate will bond strongly to the punches and the dies of tablet compression machine, thus causing sticking and other kind of surface irregularities, resulting in final product quality issues. The root cause is attributed to Clopidogrel bisulfate which easily adheres to metal surfaces of compression equipment. Because of the compression forces exerted by the upper and lower punches during tablet compression, Clopidogrel bisulfate rapidly forms a film on the surface of the punches and/or die. And because of natural adhesion, the sticking increases over time and so causes quality issues on tablet surface. During commercial manufacture, sticking is a serious problem. It is better to solve the sticking problem during formulation and process development.
European publication for EP1970054 states that the choice of diluent is very important, as the combination use of some diluents such as mannitol, mannitol with lactose or microcrystalline cellulose will enhance the intrinsic stickiness tendency of Clopidogrel bisulfate. Considered that the lubricant can help to reduce frictional forces during compression and prevent the tablet to adhere the surface of punch and die, too. Therefore one of Clopidogrel bisulfate such as hydrobromide and hydrochloride can be used as raw material with lactose, stearic acid, and one or more of other excipients to prepare tablet. It also suggests using the dry granulation equipment to prepare stable Clopidogrel tablets to solve the problem of clopidogrel hydrobromide and clopidogrel hydrochloride tablets adhering to the punch and die of the tablet compression machine.